A variety of evidence suggests serotonin 1A (5-HT1A) receptor function is abnormal in panic disorder (PD), posttraumatic stress disorder (PTSD), and depression. This project investigates the pharmacological basis for 5-HT1A abnormalities in vivo by applying positron emission tomography (PET) and the 5-HT1A receptor radioligand [F-18]FC-WAY100635 to assess 5-HT1A binding potential in PD, PTSD, and unipolar and bipolar depression. Because central 5-HT1A receptor density is down-regulated in rodents by corticosterone administration and by stress-mediated corticosterone secretion, assessments of HPA-axis activity were assessed to determine whether down-regulation of 5-HT1A receptors correlates with cortisol hypersecretion in PD, PTSD, and MDD. PET images of 5-HT1A binding were acquired in subjects who are unmedicated PD, PTSD and depressed patients, or are healthy volunteers. The 5-HT1A receptor volume of distribution was calculated with a two tissue compartment model of PET data after a bolus infusion of ([F-18]FCWAY). The 5-HT1A receptor volume of distribution in the hippocampus, amygdala, ventral ACC, and orbital cortex were compared between the depressive and control samples. The relationships between 5-HT1A receptor volume of distribution and salivary cortisol and between 5-HT1A receptor volume of distribution and cerebrospinal fluid concentrations of corticotrophin releasing hormone (CRH) were assessed by linear regression analysis. During the past year, an additional 10 subjects with MDD and 4 with BD entered into this study for 5HT1A receptor imaging; 3 of the BD subjects were rescanned following mood stabilizer treatment. We have developed satisfactory compartmental models for pixelwise determination of volume of distribution and have developed a method for defining regions of interest that will be semi-automated and thus independent of operator bias. The image data were analyzed for the BD versus control comparisons. The results include showing prominent reductions in 5HT1A receptor binding in the anterior and posterior cingulate cortices and the insula in bipolar disorder. The 5HT1A receptors in these regions play important roles in regulating emotional behavior. During the upcoming year the effects of serotonin transporter gene polymorphisms on this response will be characterized. In addition, the neuropsychological assessments from this study comparing depressed and healthy subjects have shown deficits in the unmedicated unipolar and bipolar depressed patients that are consistent with dysfunction of the amygdala, ventral anterior cingulate cortex, and orbital cortex. Specifically, unmedicated depressed patients displayed deficits in inhibiting inappropriate responses to affective stimuli that was not present in the healthy control sample suggesting an attentional bias towards these stimuli. The unmedicated depressed sample also required more time to deliberate on a risk-based task, consistent with findings in frontal lesion patients. In addition, imaging with the serotonin transporter radioligand progressed to permit characterization of the presynaptic portion of the serotonin system. An additional 8 subjects with unipolar depression, 12 subjects with bipolar depression and 8 healthy controls have been studied using this new method. These results showed for the first time a marked reduction in 5HTT sites in the brainstem and an increase in 5HTT binding in the thalamus and anterior cingulate in both bipolar depression and unipolar depression. The unipolar and bipolar depressives differed, however, in the brainstem raphe, where 5-HTT binding in the BD sample was lower than that in both the MDD and control samples. A manuscript describing these results has been published and another prepared for publication. Moreover, we have continued to characterize the relationship between ovarian steroids and 5HTT and 5HT1A receptor binding in women who develop post partum depression and menstrual related mood disorders. These data have shown that the imaging measures are sensitive to ovarian steroids. This work is being conducted in collaboration with Dr. Peter Schmidt at NIMH and with Drs. Eydie Moses and Walter Kaye at University of Pittsburgh. A manuscript describing reductions in 5-HT1A receptor binding in post partum depression currently is in review.